Cephalosporin Generations

Practice Parameter Algorithm

Testing

• Overall approach: even though standardized agents are not available, perform skin test to the cephalosporin or other beta-lactam antibiotic; if negative, perform graded dose challenge, if positive, choose alternative (vs. desensitization)

• Cephalosporin skin testing

  • Skin testing with cephalosporins is not standardized, but may be useful
    • A positive skin test result using a nonirritating concentration suggests the presence of drug specific IgE antibodies
    • A negative skin test result does not rule out an allergy because the negative predictive value is unknown
  • Skin testing to the cephalosporin followed by graded challenge is a safe method for administration of some cephalosporins in PCN allergic patients. If PCN and cephalosporin skin testing is unavailable, depending on the reaction history, cephalosporins may need to be given via graded challenge or desensitization.

Non-irritating Cephalosporin Concentrations for Skin Testing

From Drug Allergy PP 2010

• Macy: skin test with cephalosporins and other beta-lactams at 0.01 molar
• Romano: skin test with cefepime at 2 mg/mL and all other cephalosporins at 20 mg/mL
• Solensky: If skin testing with cephalosporins is desired, solutions can be prepared from IV drug preparations
  • The skin test solutions should be freshly prepared on the day of use
  • Studies have shown that:
    • 2 mg/mL (in normal saline) of several IV cephalosporins is nonirritating for SPT and ID skin testing
    • 10-fold dilutions of IV cephalosporins (10 mg/mL for ceftriaxone, cefuroxime, ceftazidime, cefotaxime and 33 mg/mL for cefazolin) were nonirritating for ID testing

• PCN skin testing

  • Patients with a history of an immediate-type reaction to a cephalosporin should undergo PCN skin testing, if available, before treatment with penicillin
    • If test results are negative, they may safely receive PCNs
    • If test results are positive, an alternate drug should be used or they should undergo cephalosporin desensitization
    • If PCN skin testing is unavailable, cephalosporin may be administered via cautious graded challenge

• Carbapenem and Monobactam Skin Testing

  • Following concentrations have been reported for SPT and ID (Romano 2014)
    • Meropenem at 1 mg/mL
    • Imipenem/cilastatin at 0.5-1 mg/mL for each component
    • Aztreonam at 2 mg/mL

Cephalosporin Cross-reactivity

Cross-reactivity between...	Notes
Cephalosporin & PCN	~2% of PCN skin test–positive patients react to treatment with cephalosporins Highest risk of cross-reactivity with 1st generation (>2nd>3rd>4th) Some fatal reactions reported
Different cephalosporins	Most hypersensitivity reactions to cephalosporins are probably directed at the R-group side chains (7 (R1) or 3 (R2) position side chain) rather than the core beta-lactam portion of the molecule. Patients with a history of an immediate-type reaction to a certain cephalosporin should avoid other cephalosporins with similar R-group side chains Similarity at the 7 (R1) position is more clinically important than similarity at the 3 (R2) position because the 3 position (R2) side chain becomes lost in the process of conjugation of the cephalosporin hapten to the carrier protein, thus only the 7 position (R1) side chain and beta-lactam ring can contribute to the epitope that may bind IgE However, cross-reactivity because of R2 side chains is possible and has been reported If you choose to treat with a cephalosporin with dissimilar side chains, the first dose should be given via graded challenge (or induction of drug tolerance), depending on severity of the previous reaction.
Cepahlosporin & ampicillin/amoxicillin	Cross-reactivity with certain cephalosporins reported in ~1/3rd (up to 38%) of patients with amoxicillin or ampicillin allergy Patients allergic to amoxicillin should avoid cephalosporins with identical R-group side chains (cefadroxil, cefprozil, cefatrizine) or receive them via rapid induction of drug tolerance Patients allergic to ampicillin should avoid cephalosporins and carba-cephems with identical R-group side chains (cephalexin, cefaclor, cephradine, cephaloglycin, loracarbef) or receive them via rapid induction of drug tolerance
Cephalospirin & monobactam	<1%, EXCEPT for ceftazidime and aztreonam Ceftazidime and aztreonam share an identical side chain and frequent in-vivo cross-reactivity has been reported In 95 patients with immediate clinical reaction + positive skin test to a specific cephalosporin (excluding ceftazidime) and a negative skin test to aztreonam (~11% with positive PCN skin test): 0% had reaction when challenged with aztreonam
Cephalosporin & carbapenem	≤1% In 97 patients with immediate clinical reaction + positive skin test to a specific cephalosporin and a negative skin test to imipenem and carbapenem (~11% with positive PCN skin test): 1% had reaction when challenged with imipenem, 0% with meropenem

Note: "R1" = 7-position

Cephalosporin Serum Sickness

• Cefaclor (and to a lesser extent cefprozil) are associated with serum-sickness–like reactions (severe erythema multiforme and arthralgias). There is no evidence of an antibody-mediated basis for this reaction. Reactions to cefaclor appear to result from altered metabolism of the parent drug, resulting in toxic reactive metabolites, which can often be documented in a parent of the patient.
• Anecdotally, patients with serum sickness–like reactions to cefaclor and cefprozil may not need to avoid other cephalosporins.\
• Solensky: serum sickness-like reactions can start after an antibiotic such as a cephalosporin or penicillin is discontinued

Cephalosporin Desensitization Protocols

IV Desensitization Protocol

Oral Desensitization Protocol (example)

Prepared from cephalosporin 250 mg/5 mL suspension

References